Atrial flutter and fibrillation are common atrial arrhythmias that are sustained by a reentrant mechanism. However, initiation of reentry requires a premature impulse which interacts with a region of unidirectional block. The proposed research is designed to understand how premature impulses are generated in the normal intact canine atria. In particular, the proposal focuses on vagal mechanisms and how they can paradoxically start tachyarrhythmias. Initial results in isolated tissue have demonstrated that acetylcholine (ACH) can spontaneously initiate fibrillation. Following a period of ACH-induced arrest, activation sequence maps demonstrated that the initial two to three closely coupled beats originated focally from separate sites followed by a transition to a reentrant pattern. the proposed mechanism of the initial focal depolarizations is the asynchronous firing of multiple atrial pacemakers accompanied by variable entrance block at later sites, inhibiting the resetting of these latent pacemakers. It is further proposed that the entrance block is due to the ACH-induced hyperpolarization of the pacemaker membranes. this proposal will investigate whether these same mechanisms function in the intact canine atrium under more normal physiologic conditions. Initially, variable concentrations of ACH will be infused into the sinus node artery at different fixed concentrations of extracellular potassium. It is anticipated, based on preliminary studies, that concentration of ACH that produce heart rates in the normal physiologic range, will generate premature betas and fibrillation in a dose-dependent manner. Furthermore, lowering the extracellular potassium level will increase the probability of ACH-induced fibrillation. Using a grid of 250 unipolar electrodes, electrograms will be simultaneously recorded and high density activation sequence maps will be constructed of any spontaneous premature beats or fibrillation. Preliminary studies have shown that ACH- induced fibrillation occurs in the presence of beta blockade. However, studies by other investigators have suggested that adrenergic tone plays an important role. We propose that the adrenergic tone is not necessary but enhances the probability of spontaneous cholinergic fibrillation. Adrenergic-cholinergic interactions will be studied by the addition of background levels of norepinephrine during ACH infusion. Because the ACH- modulated potassium channel is thought to play an important role in the entrance block, the channel will also be modulated by adenosine, which acts on the same channel independently of ACH receptors. Finally, direct vagal nerve stimulation will be performed to determine if normal patterns of neural activity can also generate premature depolarizations. First, right vagal branches will be stimulated continuously to determine which nerve initiates fibrillations. Then phasic stimulation, timed to the spontaneous atrial depolarizations, will be performed to determine the critical time during the cycle.